Friday, November 16, 2012

ASTMH 2012

I’m just back from the American Society of Tropical Medicine and Hygiene (ASTMH) 2012 meeting in Atlanta, Georgia, and once again my brain is swimming with the vast amount of information I’ve taken in.  The common theme to these meetings concerns diseases, mostly infectious, that afflict the tropical and subtropical regions of the world.  Attendees consist of medical doctors, veterinarians, disease modelers, public and global health workers, nurses, other health care workers, and social scientists, and they (we) come from all over the world.  And there appears to be a healthy mixture of students, professionals, and well-seasoned researchers.

I enjoy this meeting because many researchers and research teams present cutting edge research that I end up reading about in major journals for the rest of the year and beyond.  I was only there for two days this time around, but there were several really interesting talks to mention.

There was a lot of buzz about disappointing results with the new malaria vaccine (RTS,S), some disappointing results with regard to a dengue vaccine (it is not easily administered and doesn’t work for all strains), and decreasing sensitivity to artemisinins (blogged about here) in Africa, South America (Suriname), and some new places in Southeast Asia (Vietnam and Myanmar).  And there is debate about which is the best way to approach global health efforts.   

One symposium that I found particularly interesting concerned house architecture and vector control.  Essentially, some styles of housing are more prone to allowing mosquitoes in than are others.  For example, many of the houses in Southeast Asia are built on stilts and many of the important vectors prefer to fly low to the ground.  In the Thai villages where I work, people frequently keep livestock under their houses too, and these other large, warm blooded mammals may also act as a diversion for blood feeding insects that favor large mammals.  

Another important consideration with regard to housing and diseases concerns the comfort level of houses.  A frequently mentioned reason for not using bed nets is that they cut down on air flow at night.  I can attest that trying to sleep in the already stuffy tropics can be difficult in the absence of bed nets, let alone with them.  

Another very interesting symposium discussed some historical correlations between (frequently illegal) mining areas and malaria.  Mining areas tend to be rife with disease, perhaps especially mosquito borne disease.  These are places that have plenty of standing puddles of water (sometimes from the actual mining efforts), poor living conditions, poor sanitation, and potentially a high proportion of people who, for a variety of reasons, aren’t likely to seek and follow through with adequate medical treatment.  The symposium presenters discuss similar situations in Southeast Asia, South America, and Africa.  Anthropologists have discussed the influence of land-use patterns on human morbidity and mortality for a long time, but I think that this area of research is ripe for in depth investigation.

One of the problems with developing a vaccine for dengue is the lack of a good animal model of the disease.  However, several decades ago there weren’t such problems, medical researchers had ready access to actual human models in the form of ‘volunteers’ (frequently from prisons!)

Dr. Albert Sabin, who developed the oral, live attenuated polio virus, also worked toward the development of a dengue virus.  He infected over a hundred volunteers, kept track of their symptoms (including the timing of fevers), and then later re-infected them with another strain in order to look for immunity (strands DENV-1 and DENV-2).  He wrote a famous paper on his results in 1952 but the details of his experiment weren’t made public.[1]  However, he bequeathed his lab notebook(s) to Duane J. Gubler at the Duke-NUS Graduate Medical School in Singapore and some of the results (including some truly fascinating hand-drawn plots) were presented at the meeting by Gubler and several colleagues.  

One surprising finding was that none of the volunteers developed dengue hemorrhagic fever upon subsequent infection.  People who have been infected by one of the four strains of dengue appear to have some immunity.  However, that immunity is strain specific and reinfection with another strain is associated with much more severe symptoms, including dengue hemorrhagic fever and dengue shock syndrome.  For some reason, the volunteers in Sabin’s experiments didn’t develop these more severe symptoms.  (The presenter also noted that the vast majority of volunteers were middle-aged white males.  It could be that these strains don’t act as the others do, that there are some human host factors that are important, or a variety of other possibilities.)  Sabin’s research also indicated that strain-specific immunity appears to wane quickly (8 – 10 weeks).  

And one last symposium that I’ll mention was titled “Adventures in Tropical Dermatology”.  I learned a few things from this discussion, all of which I’m glad I learned in a nice hotel in Atlanta, Georgia rather than first hand in the field.  One of the more surprising to me concerned lobomycosis, a pretty terrible looking skin disease that humans can contract from dolphins.  I’ll spare you the nasty pictures but a simple google image search will result in plenty of images.  But if you’ve ever had dreams of swimming with dolphins, perhaps especially in Latin America, you might reconsider…

Monday night there was a discussion by Michael Alpers, one of the researchers who discovered kuru; a severe brain disease resulting from exposure to infectious prions.  Prions are oddly shaped proteins and prion infection seems to occur when these oddly shaped proteins come into contact with normal proteins, leading those proteins to become oddly shaped as well.  The result is porous neural tissue that resembles something like Swiss cheese.  Kuru has an extremely long incubation period, taking many years (5 – 20) to actually set in.  The group of scientists who discovered prions had to be extremely patient in their research, and had to persistently put their bold ideas about a new pathogenic agent in front of a frequently harsh scientific audience.  Alpers noted that Prusiner (another member of the research team) received a lot of abuse from scientific audiences when he began talking about the potential existence of prions.  

While prion infection is a widely accepted concept today, there is still a whole lot we don’t understand.  I think it’s relatively safe to say the same about most diseases, even the ones we’ve known about for centuries.  

My takeaway lessons from ASTMH 2012 are as follows:

  • Universal fixes to diseases almost always remain elusive
  • Long term fixes for most any disease are probably only going to come from multiple, diverse approaches 
    • This means that collaboration across sub-disciplines and fields is extremely important!
    • And many approaches will need to be place-specific
  • While we might be able to eradicate diseases from some areas, it is important to have community involvement and to address more distal, upstream socio-economic and political issues so that those diseases doesn’t simply return
  • Disease ecology, like most of life, is extremely complex

***I have clearly glossed over a LOT of other really good symposiums, posters, and talks***

1.        Sabin AR (1952) Research on dengue during World War II. American Journal of Tropical Medicine and Hygiene 1: 30 – 50. 


Ken Weiss said...

One way to combat the problem that intense application of an anti-parasite compound like a single drug is that as a result of the intensity of natural (actually, artificial) selection, the parasite population is forced to, and is able to, evolve genetic resistance. Resistant organisms find themselves without competition from their susceptible fellows, and can reproduce rapidly.

From an evolutionary point of view, is it not correct that one idea in the case of diseases like dengue and malaria is to clobber the parasite out of existence if possible, rather than have to continue to combat it by continual symptomatic treatment?

This is what rarely seems to work, because of parasite resistance evolution. The same is true with resistance to chemotherapy in cancer patients.

So, one approach has been to apply major doses of more than one drug at the same time. This raises the likelihood, in theory at least, that no parasite individual (or individual tumor cell) will resistance to all of the agents hunting them down, before all of the parasites are gone.

Is such multi-component targeting part of the strategy in relation to dengue or malaria?

Marnie said...

Hi Anne,

Thanks for all the amazing recent posts. At some point, I'd be interested on your thoughts on this paper:

Signatures of Environmental Genetic Adaptation Pinpoint Pathogens as the Main Selective Pressure through Human Evolution

Matteo Fumagalli et al.

Marnie said...

Regarding the need to build houses that are less prone to mosquitos, ones that are ventilated, liveable and also built off the ground, I stumbled on this article in Dwell Magazine a few years ago:

An inno-native approach:

Marnie said...

Sorry, my post should be addressed to Daniel, as I see he is the author.

Unknown said...

By multi-component targeting, do you mean using multiple drugs that are likely to target different aspects of the parasite or virus? If so, yes, that is the common recommendation for treatment of falciparum malaria. Artemisinin (which is the last drug without widespread resistance) is supposed to only be used in combination with other antimalarials that are thought to have different modes of action or targets and certainly have different half-lives. Artemisinin has a half life of hours whereas other drugs in the cocktail have half-lives of weeks or more.
There really aren't any drugs for treating dengue yet, but I imagine that after there are, and after drug resistance emerges with dengue, that drug cocktails will be the next move for dengue too.

Ken Weiss said...

Yes, that's what I meant.

Anne Buchanan said...

I'll say thanks very much from all of us, Marnie, as we've all been posting recently. I was trying just today to figure out how to move the author's name up under the post title, but couldn't. I know it's confusing as it is. If anyone knows the secret in Blogger, please let me know!

I'll turn responding more fully to the paper you've linked to over to Ken, as he's the one with more to say on the subject of selection and the human genome. Except that I will say that this paper reports finding signatures of selection at immune genes; while GWAS have been pretty unsuccessful at finding genes for disease in general, over and over they _do_ report at least some association of whatever disease with immune genes as well. This starts to look like real evidence that disease might in fact have been a strong selective force. We know that's true for malaria. Which other diseases it might also be true for I think is still an open question.

Unknown said...

Some nations have been pretty slow to make combination therapy the official approach to treating malaria. For that matter, in many places local distributors (with no medical training and sometimes fake or substandard drugs) are the main outlet for antimalarials.

Also, in some places they are now treating vivax malaria with combination therapy (Cambodia is one place.) However, in Thailand they still treat vivax with chloroquine. Falciparum is widely resistant to chloroquine and it is thought that mixed infections (people infected with both vivax and falciparum) might lead to sustained resistance of falciparum to chloroquine.

Unknown said...

Hi Marnie, thank you very much for passing this on. I had not seen it.

Unknown said...

And perhaps another interesting evolution / drug resistance story has been the suggestion that we should consider not using aggressive therapy (high doses of antimalarials). I'm oversimplifying the argument, but basically the idea is that aggressive therapies more quickly lead to drug resistance.

Marnie said...

Daniel and Anne,

The Matteo Fumagalli et al. paper finds that pathogens are a dominant cause of selection in humans. Moreover, among pathogens, it's helminths that impose the clearest selection signature.

This really jibes with my observations of West Africa. Malaria is definitely a killer, but its victims are often children who don't live long enough to have children of their own.

Not so for helminth infections such as dracunculiasis. People often live with these for many years.

An interesting thing about dracunculiasis is that it will probably be more or less eliminated by communicating how it is transmitted, by providing access to clean water and by wearing shoes.

Thank you for your very timely recent posts.

Ken Weiss said...

The paper and its authors are very respectable and their generic conclusion seems plausible. I have only had a chance to look very superficially at it. However many things are correlated with pathogenic exposure so inferences are still rather speculative.

On the other hand, many mapping studies are finding immune or inflammation related genes associated with chronic diseases that hadn't seemed related to infection, so the story again makes plausible sense.

Of course, infection and inflammation are very generic kinds of reactions, and even finding 100 such gene regions needs to be seen in perspective.

Traits that have possible human adaptive influences involve many things unrelated to inflammation (body size and shape and color and so on). Strong single-gene signals are few and far between. And since most traits of interest are complex, the effect of selection can be distributed across the contributing genes, to the extent that they might not be detectable at any one of them.

These comments address your idea that pathogens are a 'dominant' cause, rather than just one of many possible causes.

Infectious agents can impose very strong selection and rapid evolution, so the paper's findings are not surprising. How that works in the populations in which the data are found, which have traditionally been very small and widely dispersed, is a different question because of patterns of transmission require adequate host-demography. Perhaps the paper addresses this.

As to your comments about children, I don't understand. Early mortality in children is extremely strong selection against their genotypes, and if helminths let you live long, that would _reduce_ their selective intensity, so that is something you should think about (or that I misunderstand from your comment).

Hopefully measures such as you suggest will make any selective impact--and any disease impact--go away in the future.

Anne Buchanan said...


What you say about dracunculiasis, that it will likely be eliminated by the use of clean water and the wearing of shoes, echoes the greatest public health successes. Clean water arguably has done the most for health world wide than any medication ever will. Window screens are up there, too. The solution is often nothing fancy, though it does always involve money. And, of course, as Daniel has been pointing out, evolution can be counted on to make the fancy stuff obsolete before a new solution can be developed.

Marnie said...

Most Africans will tell you themselves that they know that disease risk would be mitigated with improved access to clean water. But even that isn't easy in an area where the climate alternates between drought and gushing rainy seasons.

When we lived in Ghana, my mom at one point was thinking about no longer boiling our water. Once she had a look in the reservoir, she changed her mind. There was a dead lizard and a dead snake in it. I think that illustrates how difficult it can be to maintain a clean water supply in the tropics.

As a child there, I actually got some kind of helminth infection. As all children invariably do, I fell and scraped my knee. It soon became strangely infected and started to migrate. I was lucky and was given a massive dose of antibiotics by injection. Most Ghanaians, especially at that time, would not have had access to such a treatment.

Many who do not or have not lived in Africa often do not understand that living in the tropics presents very different challenges than living in a temperate climate.

Ken Weiss said...

These are very good points.

I have seen the same thing in rural Mexico, and did a bacterial (diarrheal) study in which we found that even the well water (much cleaner than the green-scum covered village pond) was contaminated. The greatest victims seemed to be infants threatened by diarrhea, but probably everyone was at some risk (my stay was only a couple of days, so not enough to make any judgements except that we did see affected infants)